Frontier Center for Organic Materials, Yamagata University, 4-3-16 Jonan, Yonezawa, Yamagata 992-8510, Japan; Innovative Flex Course for Frontier Organic Material Systems, Yamagata University, 4-3-16 Jonan, Yonezawa, Yamagata 992-8510, Japan; Research Center for Functional Materials, National Institute for Materials Science, 1-1 Namiki, Tsukuba, Ibaraki 305-0044, Japan.
Exp Cell Res. 2018 Sep 15;370(2):571-578. doi: 10.1016/j.yexcr.2018.07.022. Epub 2018 Jul 18.
Chemoresistance is one of the major barriers for tumor chemotherapy. It is clinically known that chemoresistance increases during tumor progression. Additionally, the extracellular matrix (ECM) is also remodeled during tumor progression. However, it remains unclear how ECM remodeling contributes to chemoresistance acquisition. Recently, it has been reported that epithelial-mesenchymal transition (EMT) contributes to chemoresistance acquisition. Here, how ECM remodeling contributes to 5-fluorouracil (5-FU) resistance acquisition was investigated from the viewpoints of EMT using in vitro ECM models mimicking native ECM in colorectal tumor tissue at three different malignant levels. 5-FU partially induced EMT and increased ABCB1 in colorectal HT-29 cells via TGF-β signaling (an invasive tumor cell model). When HT-29 cells were cultured on an ECM model (high malignant matrices) mimicking native ECM in highly malignant tumor tissues, the cells facilitated TGF-β-induced EMT and increased ABCB1 upregulation compared with that of other ECM models mimicking the low malignant level and normal tissues. High malignant matrices contained more chondroitin sulfate (CS) chains than those of other ECM models. Finally, CS chain-reduced high malignant matrices could not facilitate ABCB1 upregulation and TGF-β-induced EMT. These results demonstrated that ECM remodeling during tumor progression increased CS chains to facilitate EMT and ABCB1 upregulation, contributing to chemoresistance acquisition.
化学耐药性是肿瘤化疗的主要障碍之一。临床上已知，随着肿瘤的进展，耐药性会增加。此外，细胞外基质（ECM）在肿瘤进展过程中也会重塑。然而，目前尚不清楚 ECM 重塑如何促进获得化疗耐药性。最近，有报道称上皮-间充质转化（EMT）有助于获得化疗耐药性。在这里，我们从 EMT 的角度，利用三种不同恶性程度的结直肠肿瘤组织中模拟天然 ECM 的体外 ECM 模型，研究 ECM 重塑如何促进 5-氟尿嘧啶（5-FU）耐药性的获得。5-FU 通过 TGF-β 信号通路（侵袭性肿瘤细胞模型）部分诱导 EMT，并增加结直肠 HT-29 细胞中的 ABCB1。当 HT-29 细胞在模拟高度恶性肿瘤组织中天然 ECM 的 ECM 模型（高度恶性基质）上培养时，与模拟低度恶性水平和正常组织的其他 ECM 模型相比，细胞促进 TGF-β 诱导的 EMT，并增加 ABCB1 的上调。高度恶性基质比其他 ECM 模型含有更多的硫酸软骨素（CS）链。最后，CS 链减少的高度恶性基质不能促进 ABCB1 的上调和 TGF-β 诱导的 EMT。这些结果表明，肿瘤进展过程中的 ECM 重塑增加了 CS 链，促进 EMT 和 ABCB1 的上调，从而导致化疗耐药性的获得。
